Central nutrient sensing of the essential amino acid l-leucine is a critical determinant of food intake and meal size. We have shown that: 1) endogenous central levels of leucine are rapidly elevated after a meal, 2) blocking endogenous leucine catabolism within the mediobasal hypothalamus (MBH), thereby promoting local leucine availability, reduces food intake, 3) MBH leucine administration reduces food intake by reducing meal size, 4) blocking downstream intracellular cascades of leucine signaling in the MBH promote feeding, while 5) chronic activation of these downstream pathways in the MBH limit high fat diet hyperphagia and associated weight gain. These actions appear to be mediated by two intracellular signaling pathways: the mammalian target of rapamycin (mTOR) - serine/threonine kinase p70S6K (S6K) pathway, and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. MBH leucine at feeding inhibitory doses also activates the brainstem dorsal vagal complex of the caudal brainstem, particularly the caudomedial region of the nucleus of the solitary tract (cmNTS), where meal-related gut negative feedback signals converge and are integrated to mediate the neural control of meal size. Our recent published and preliminary results support the identification of the cmNTS as a site where local leucine acts to reduce food intake by limiting meal size and by increasing the feeding inhibitory potency of CCK. These actions appear to be mediated by both mTOR-S6K and ERK pathways as well. Furthermore, diet induced obesity (DIO) attenuates cmNTS leucine's feeding inhibitory actions. Taken together, these data suggest a new brainstem nutrient sensing capability, and its novel integration with direct controls of meal size. Studies in this proposal will apply a coordinated combination of behavioral, neurophysiological, pharmacological, immunohistochemical and molecular genetic approaches to identify and characterize the neural and molecular mechanisms underlying brainstem nutrient sensing in the control of feeding, how it is disrupted in DIO, and how it can be targeted to control food intake and body weight in obesity.